Aging‐related carcinoembryonic antigen‐related cell adhesion molecule 1 signaling promotes vascular dysfunction

Abstract

Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that TNF‐α is CEACAM1‐dependently upregulated in the aging vasculature. Vice versa, TNF‐α induces CEACAM1 expression. This results in a feed‐forward loop in the aging vasculature that maintains a chronic pro‐inflammatory milieu. Furthermore, we demonstrate that age‐associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age‐dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR‐2 signaling. Consequently, aging‐related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…However, the main function of HIF-1α is the inhibition of the proliferation and migration of human VSMCs, indicating that HIF-1α induces VSMC phenotype switching [150]. However, stabilization of the HIF-1α protein in 9-month-old WT mice promoted increased endothelial permeability [152].…”

CEACAM1 promotes vascular aging processes

“…A hallmark of vascular aging is the increased deposition of collagen fibers within the media of larger vessels. Intriguingly, we found that only in the presence of CEACAM1 vascular aging in mice was accompanied by vascular fibrosis presumably due to enhanced TGFβ/TGF-βR1 signaling whereas genetic deletion of CEACAM1 completely prevented aortic collagen accumulation [1]. Our in vitro data suggest that CEACAM1 modulates endothelial TGF-β/TGF-βR1 signaling in a TNF-α-dependent manner [1].…”

“…Since we showed previously that CEACAM1 is critically involved in TNF-α-mediated endothelial barrier breakdown via adherens junction disassembly [3], we wondered whether CEACAM1 might also contribute to vascular aging. As a first hint, we observed re-expression of CEACAM1 in the murine and human vasculature with progressive age [1]. This upregulation of vascular CEACAM1 expression is of great importance since we demonstrated that the presence of CEACAM1 is necessary for age-associated vascular upregulation of TNF-α using a murine CEACAM1 knockout model.…”

“…This upregulation of vascular CEACAM1 expression is of great importance since we demonstrated that the presence of CEACAM1 is necessary for age-associated vascular upregulation of TNF-α using a murine CEACAM1 knockout model. Reversely, TNF-α induced the expression of CEACAM1 in cultured endothelial cells, indicating the establishment of a vicious cycle within aging vessels [1].…”

“…Therefore, novel targets are required to modulate age-dependent processes. Carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1, CD66a) is a glycoprotein of the immunoglobulin superfamily [1] . Concerning the vasculature, CEACAM1 contributes to angiogenesis by induction of vascular sprouting, promotes morphogenesis and is involved in initial endothelial barrier establishment [2,3].…”